Alkamine esters of delta-cyclohexenylalkylacetic acids



Patented Jan. 23, 1951 NITED STATES PATENT OFFICE 2,538,794 E ESTEES F ACYCLOIIEXENYL- AIKYLAGETIO ACIDS Robert Bruce Moflett, Kalamazoo, Mich.,and

Charlotte Anne Hart, Kansas City, Mo., assignors to George A. Breon andCompany,

City, Mo., a corporation of wssouri No Drawing. Application August 10,1948, Serial No. 43,543

, 1 This invention relates to aminoalkyl esters of A-cyclohexenylalkylacetic acids and to therapeutically acceptable saltsthereof which are useful as antispasmodic agents. This is acontinuationin-part of our copending application, S. N. 642,427, filedJanuary 19, 1946,

These esters have the formula where R is an alkyl group of 4-6 carbonatoms, Y is an allrylene bridge having at least two carbon atomsseparating the oxygen and nitrogen atoms, and -N=B is a tertiary-aminogroup wherein B represents two alkyl groups or the atoms neces sary tocomplete a heterocyclic ring. More specifically Y may be a divalenthydrocarbon radical such as ethylene, propylene, butylene, l-methyl-=ethylene, Z-methylethylene or l-methylbutylene; and -N=B includes suchstructures as dimethylamino, ethylmethylamino, diethylamino,dipropylamino, dibutylamino, butylpropylamino, piperidyl,z-methylpiperidyl, morpholinyl, thiomorpholinyl,beta-hydroxyethylethylamino, etc. These may be classed together asaliphatic tertiary-amino groups; the heterocyclic rings are distinctlynon-aromatic in character and can be thought of as two alkyl groupsjoined together by a divalent bridge such as CHz-, -O- or S.

These compounds are generally used in the form of water-solubleacid-addition salts or quaternary ammonium derivatives. The acids whichmay be used to prepare the salts are those which produce, when combinedwith the basic esters, salts whose anions are relatively innocuous tothe animal organism in therapeutic doses of the salts, so that thebeneficial physiological properties inherent in the basic esters are notvitiated by side-effects ascribable to the anions. Appropriate acidaddition salts are those derived from mineral acids such as hydrochloricacid, hydrobromic acid, hydriodic acid, and sulfuric acid; and organicacids such as acetic acid, citric acid and tartaric acid. The quaternaryammonium derivatives are obtained by the addition of alkyl or aralkylesters of inorganic acids or organic suli'onic acids, such as methylchloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride,benzyl chloride, benzyl bromide, methyl sulfate, methylbenzenesulfonate, methyl-p-toluenesulfonate, etc.

Synthetic antispasmodics usually have both a musculotropic(papaverine-like) action and neurotropic (atropine-like) action. It isdesirable that new compounds be introduced which have high neurotropicactivity but which lack the characteristic undesirable physiologicalside-effects of atropine.

Our compounds are distinguished by h h neurotroplc activity, and, inaddition, several mem= bers of the series show antihistaminic action.

Our compounds are conveniently prepared by esterification of thecorresponding substituted acetic acid, (Col-I9) --CHR-COOH. The acidsthemselves are prepared in the following manner. The sodio derivative ofdiethyl n -cyclohexenylmalonate, (Cal-Is) -CH-(C0OC2H5) r, is alkylatedwith RX, where R is an alkyl group of 4-6 carbons and X is a halogenatom, i. e., chlorine, bromine or iodine. The resulting AF-cyclohexeny w1 malonic ester, (CsH9)-CR-(COOC'2H5) 2, is hydrolyzed by heating with30% alcoholic potassium hydroxide in a bomb at -150" 0., anddecarboxylated at C. at atmospheric pressure, giving the desired A-cyclohexenylalkylacetic acid.

In some cases where the malonic esters are diflicult to prepare becauseof the steric hindrance of the groups involved, an alternative procedurecan be used. This is based on the method of Alexander and Cope [J. Am.Chem. Soc. 66, 886 (1944)]. which involves condensation 01' an aldehydeor ketone with ethyl cyanoacetate and reduction of the resultingethylenic double bond, all carried out in one step. In preparing thecompounds of the present invention the carbonyl compound used has astructure such that the group R in the resulting substituted cyanoaceticester, R-CH(CN)-COOCzHs, has 4-6 carbon atoms. For example, condensationof ethyl cyanoacetate and methyl isopropyl ketone in the presence ofammonium acetate, acetic acid and alladium-on-charcoal in an atmoshereof hydrogen gives ethyl (1,2-dimethylpropyl) -cyanoacetate. Thesodio-derivative of the mono-substituted cyanoacetic ester in thenalkylatedwith a A -cyclohexenyl halide to give an ethyl Acyclohexenylalkylcyanoacetate,

(CeHo) CR(CN) COOC2H5 This is hydrolyzed and decarboxylated to thecorresponding A -cyclohexenylalkylacetic acid, (CeH9)-CHRCOOH, althoughin lower yield than the hydrolysi and decarboxylation of thecorresponding malonic ester. Substituted acetamides appear as byproductsand more drastic conditions of hydrolysis lead to decomposition.

Instead of alkylating malonic ester, 9. substituted malonic ester orsubstituted cyanoacetic ester with a A' cyclohexenyl halide, it is oftenpreferable to use the more readily available 1,2- dibromocyclohexane.The simple alkylation product, a 2-bromocyclohexylmalonic or cyanoaceticester, is not obtained. Under the conditions of the reaction, hydrogenbromide is lost giving rise to the desired 2-3 double bond.

The preferred method, the malonic ester or cyanoacetic ester synthesis,in a given case depends upon the nature of the alkyl group to beintroduced. 11 the alkyl group to be introduced is of the straight chaintype or is branched at the end, themalonic ester synthesis is preferred.

If the alkyl group is branched, particularly near its point of juncturewith the rest of the molecule, the cyanoacetic ester method ispreferred.

The esters of our invention, having the general formulaCeH9CH(R)COOY-N=B as described above, and their acid addition salts, areprepared from the free acid by one of the following methods.

(1) An acid halide or anhydride of a A -cyclohexenylalkylacetic acid isreacted with a tertiaryaminoalkanol of the formula HO-Y-N=B, where Y isan alkylene-bridge of at least 2 carbon atoms and N=B is atertiary-amino group. The reaction is effected by simple admixture ofthe two components although heating is generally used to accelerate thereaction; The free basic ester is obtained by addition of alkali to thereaction mixture. verted to an acid addition salt by the addition,

preferably in non-aqueous medium, of a therapeutically acceptable acid,such as hydrogen chloride in alcoholic solution.

The basic ester may be con-' to dissolve soluble salts and the organiclayer is separated, washed with water and dried over (2) The A-cyclohexenylalkylacetic acid is re-.

(4) A metallic salt of a A -cyclohexenylalkyl- I acetic acid is heatedor simply mixed with a tertiary-aminoalkyl halide. In this case the freebasic ester is formed directly.

Quaternary ammonium salts are prepared by mixing the free basic esterwith a lower alkyl or aralkyl ester of a strong inorganic acid ororganic sulfonic acid, preferably in an inert organic solvent such asbenzene or ether, with or Without gentle heating. The salt eithercrystallizes immediately or can be obtained by concentration of thesolvent.

EXAMPLE 1 (a) Diethyl M-cyclohexenZ/Zmalomzte.-To a solution of 184 g.(8 m.) of sodium in 2.8 liters of absolute ethanol is added 641 g. (4m.) of diethyl malonate and then 968 g. (4 m.) of 1,2-dibromocyclohexaneis slowly run in. After refluxing for six hours the mixture ispractically neutral. Most of the alcohol is then removed by distillationand the residue is diluted with 1 liter of water. The layers areseparated and the organic layer is washed with water, dried overanhydrous sodium sulfate and distilled from a Claisen flask. Thefraction distilling at 88-130 (0.1 mm.) is redistilled through anefficient column, giving about 625 g. (65%) of diethyl A-cyclohexenylmalonate, B. P. 87; C. (0.11 mm.); np =l.4595; d4 =1.0443.

(b) Diethyl A -cycloheccenyl-isoamylmalonate. --To 17.3 g. (0.75 m.) ofsodium melted under 150 cc. of dry toluene in a 1 liter flask is slowlyadded, with vigorous stirring, 180 g. (0.75 m.) of diethyl A-cyclohexenylmalonate. The mixture is refluxed until practically all ofthe sodium has reacted, and then 136 g. (0.9 m.) of isoamyl bromide isadded. After refluxing for twelve hours the reaction mixture is cooledand neutralized with acetic acid. Enough water is added anhydrous sodiumsulfate. After removal of low-boiling solvents, the product is distilledat reduced pressure, first from a modified Claisen flask and thenthrough an efilcient column giving about 113 g. (48.5%) of diethyl A-cyclohexenyl-isoamylmalonate, B. P. 97 C. (0.02 mm.) n =1.4643; d4=0.9993.

(c) A cyclohexenyZ-isoamylacetic acid.--A mixture of 40 g. of diethyl A-cyclohexenyl-isoamylmalonate with a solution of 40 g. of potassiumhydroxide in 100 cc. of 95% ethanol is heated on a bomb in an oil bathat -160 C. for three hours. After cooling, the contents are diluted withwater, extracted with ether and acidified with hydrochloric acid. Theproduct is extracted with ether, and the ether solutions then washedthoroughly with water and dried over anhydrous sodium sulfate. Afterremoving the solvent, the product is heated to C. until carbon dioxideceases to be evolved, and then is distilled at reduced pressure fromaClaisen flask, giving about 28 g. of A cyclohexenyl-isoamylacetic acid,B. P. 104 C. (0.07 mm.); n =1.4746; d4 =0.9669.

(d) Beta-diethylaminoethyl A -cyclohexemllisoamylacetate and itshydrochZoride.A-cyclohexenyl-isoamylacetic acid (21.8 g., 0.104 m.) isneutralized to phenolphthalein with alcoholic sodium ethoxide, and 14.1g. (0.014 m.) of betadiethylaminoethyl chloride in 40 cc. of isopropylalcohol is then added. After standing for several days (or refluxing forseveral hours), the sodium chloride is removed by filtration, and thevolatile solvents are distilled off. The basic ester is dissolved inether, washed with water and extracted with cold dilute hydrochloricacid. The acid solution is washed with ether and made basic with sodiumcarbonate. The liberated basic ester is extracted with ether and theether solution is dried over anhydrous sodium sulfate. Distillation ofthe product at reduced pressure after removal of the ether gives about17.4 g. (54%) of beta-diethylaminoethyl A -cyclohexenyl-isoamylacetate,B. P. 109 C. (0.029 mm.); n =1.466O; d4 =0.9285.

The hydrochloride of beta-diethylaminoethyl A-cyclohexenyl-isoamylacetate is prepared by passing dry hydrogenchloride gas into a solution of 16.1 g. of the free basic ester inabsolute ether. A colloidal precipitate forms which crystallizes uponstirring. After filtering, washing with ether and drying, thehydrochloride is obtained; weight 10.8 g. (60%). Upon recrystallizationfrom methyl isobutyl ketone it has the M. P. l01-105 C.

EXAMPLE 2 (a) A -cyclohexenyZ-isoamylacetyl chloride- A solution of 44g. (0.21 m.) of .A -cyclohexenyl-isoamylacetic acid in 36.3 cc. ofthionyl chloride is warmed at 50 C. until the reaction is complete. Theexcess thionyl chloride is removed at reduced pressure and the productis distilled giving about 45 g. (94%) of M-cyclohexenyl-isoamylacetylchloride, B. P. 85 C. (0.07 mm.); n =1.4800; d4 =1.0017.

(b) Beta-dimethylaminoethyl A -cyclohezcenylisoamylacetate and itshydroohlorida-Beta-dimethylaminoethanol (7.8 g., 0.088 m.) is dissolvedin 70 cc. of dry pyridine and 20 g. (0.088 m.) of A-cyclohexenyl-isoamylacetyl chloride is added, and the mixture is'allowed to stand for a few minutes and finally heated on a steam bathfor four hours. After cooling the mixture, it is shaken with a solutionof 8 g. of sodium carbonate monohydrate in 150cc. of water and the waterlayer is separated and extracted with ether.

"The combined organic layers are concentrated using a water aspiratorand the residue distilled at reduced pressure, giving about 21.7 g.(89%) of beta-dimethylaminoethyl A -cyclohexenylisoamylacetate, B. P. 93C. (0.015 mm.)

The hydrochloride is prepared in the manner described in Example 1, partd by passing dry hydrogen chloride gas through a solution of the basicester in anhydrous ether. The hydrochloride is obtained in about 46%yield and has the M. P. 114-115 C.

EXAMPLE 3 Beta- (N-piperidyl) -ethyl A-cycIohewenyZ-isoamylacetate.-This is prepared by the same methoddescribed in Example 2, using as starting materials A-cyclohexenyl-isoamylacetyl chloride and beta-(N-piperidyl) -ethanol.'The product is obtained in about 77% yield and has the B. P. 130 C.(0.01 mm.); n =1.4832; d4= =0.9768.

The hydrochloride of beta-(N-piperidyl) -ethyl A-cyclohexenyl-isoamylacetate is prepared in the usual manner from thefree basic ester and hydrogen chloride gas in ether solution. It isobtained in about 76% yield and has the M. P.

urated sodium chloride solution and dried over anhydrous sodium sulfate.After removing the solvent, the product is distilled at reducedpressure, first from a Claisen flask and then through a 12-inch columnpacked with %-inch glass helices, giving about 110 g. of ethyl A-cyclohexenyl-sec-butylcyanoacetate, B. P. 94 C. (0.02 mm.); n =1.4'750;d4= =1.0015.

(b) A -cyclohexenyl-sec-butylacetic acid.A mixture of 40 g. (0.16 m.) ofethyl M-cyclohexenyl-sec-butylcyanoacetate with a solution of '70 g. ofpotassium hydroxide in 120 cc. of 90% ethanol is heated in a bomb in anoil bath at 140-180 C. for 43 hours. After cooling, the contents of thebomb are diluted with water, extracted with ether to remove considerableneutral material, and acidified. The acidic oil is extracted with ether,washed three times with water and once with saturated sodium chloridesolution containing a little sodium bicarbonate, and finally dried overanhydrous sodium sulfate. After removal of solvent, the product isdistilled at reduced pressure from a Claisen flask, giving about 21.6 g.(69%) of N-cyclohexenyl-sec-buty1- acetic acid, B. P. 92 (0.01 mm.); n=1.4800; d4* =0.9912. I

(c) Beta-diethylaminoethyl A -cyclohexenylsec-butylacetate and itshydrochlorida-This is prepared from the substituted acetic acid usingsodium ethoxide and beta-diethylaminoethyl chloride according to themethod shown in Example 1, part d- Nine and six-tenths grams of acidresults in about 8.6 g. (60%) of beta-diethylaminoethyl A cyclohexenylsec butylacetate, B. P. 109 C. (0.04 mm.) n =1.4701;

The hydrochloride is prepared in the usual manner from the basic-esterand dry hydrogen chloride gas in ether solution. When recrystallizedfrom methyl isobutyl ketone, the hydrochloride melts at 105-110 C.

Additional compounds have been made by the methods outlined in thepreceding examples and are disclosed in the following table.

TABLE I A. Malonates Oocoooimn it B B. P. O.( mm.) m)" d4" CH1(CH1):(0.09) 1.4638 1.0071

CBhCHCHaCHr- 07 (0. 02) 1. 4643 0. 9993 CHaCHaCHCHa- 98 (0.018) 1.4848 1. 0071 CHIOHICHCHr- 100 (0. 026) 1. 4684 0. 9984 OH; H]

B. Cyanoacetates ON 61-0 0 0 01H 1:

R B. P. O. mm.) up" (14" emotion.- 02 0.05) 1. 4127' 0. 9913 CHaCHaCK-94 (0. 02) 1. 4750 l. 0016 CHgCHaCHgCH- 101 (0.05) 1.4750 0.9882

. CHsCH-CH- 96 (0. 045) 1. 4778 0. 9974 O. Acetic acids OCH-C 0 on R B.P. C.( mm.) no" d4" CHKCHDF' 102 (0. 006) 1. 4770 0. 9818 CHaCHCHzCHr:104 (0.07) 1. 4746 0.9669

HI CHQCHgCHCHi- 103 (0. 03) 1. 4758 0.9715

H: CHaCIfiCH-Cfir- 111 (0. 026) 1. 4775 0. 9600 CH: Ha I CHICHCHI- (0.013) 1. 4754 0. 9810 a CHsCHaCH- 92 (0. 01) 1. 48m 0. 0912 0 HICH'CHCHCH 106 (0. 046) 1. 4790 0. 0778 H: CHgOH-CH- 108 (0. 04) I 1.4806 TABLE I; Basic eaten as; R -5158 CHQOHI l CBKCHnh- I 5-CHQCH5N 118(0.2)

omen:

2 cmcncm- CH1CH|N 108 (0.01)

n, omen:

omen,

a cmcncmcnr- -CH|0H 100(0020) H1 CH1CH:

CH0 4. cmcrrcmcm- -CH1OHiN 93(0015 H: CHa

011103: 6.. cmcncmcm- 0H,c11,1-1 cm 130 (0.01) Hz CHgC:

cmcm

a. cmcmcn- CH|CH: 100 (0.04

H: CHaCHI CHSCHI 7 cmcmcncm- CHCH2N 11001025 H, cmcm a cmcmcmca- CH:CH1N130 (0.5)

(1H0 CHaCHa CHzCHa 9 cmcn-on- 4321:0115 124(015) H: H, 035cm CHzCH: v

10.- cmcnwncm- CH:CH;N 1140.010)

OH: H: CHsCH:

N=B is a tertiary-amino group of the class Hydw consisting ofdi-lower-alkylamino, piperidyl and Compound "D a." chloride morpholinylradicals; and acid addition and quaternary ammonium salts thereof.

2. A substance of the group consisting of basic 103-10415 esters of theformula 0. 9324 102-104 OH-CO OYN wherein R is an alkyl group of 4-6carbon atoms,

We-clalm: Y is an alkylene bridge of 2-5 carbon atoms and R and R" arelower alkyl groups and acid 1. Asubstance f the u 0 ns t f esters of thefomgula gm p 0 15 mg 0 baslc addit1on and quaternary ammonium saltsthereof.

3. A substance of the group consisting of basic esters of the formulawherein R is an alkyl group of 4-6 carbon atoms, 76 Y is an alkylenebridge of 2-5 carbon atoms and 1; CH5.

wherein R is an alkyl group of 4-6 carbon atoms and Y is an alkylenebridge of 2-5 carbon atoms; and acid addition and quaternary ammoniumsalts thereof.

4. A substance of the group consisting of the formula CHaCHsCH-COO-CHaCHz- CHaCHa wherein R is an alkyl group of 4-6 carbon atoms,and acid addition and quaternary ammonium salts thereof.

5. A substance of the group consisting of betadiethylaminoethyl A-cyclohexenyl-isobutylacetate of the formula CHsCHa CH-COO CHaCHaNHr-CH-CH: CHaCH:

and acid addition and quaternary ammonium salts thereof.

6. A substance of the group consisting of betadiethylaminoethyl A-cyclohexenyl-isoamylacetate of the formula CHxCHa CH-C O O CHaCHaN(JHaCHaCI-ICH; CHICK:

and acid addition and quaternary ammonium salts thereof.

7. A substance of the group consisting of beta- (N-piperidyl) -ethyl A-cyclohexenyl-isoamylacetate of the formula CHICHI CH-COO CHICHIN CH2HaCHaGHCH: OHaC and acid addition and quaternary ammonium salts thereof.

10 8. A substance of the group consisting of betadiethylaminoethyl A-cyclohexenyl-(1,2-dimethy1propyl)-acetate of the formula CHaCHI CH-C OO CHICHIN H-CH-CH: CHlCHI CH-CO 0 CHaCHs (JHQCHzCHCHs OH:

and acid addition and quaternary ammonium salts thereof.

ROBERT BRUCE MOFFE'IT. CHARLOTTE ANNE HART.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 1,677,123 Adams July 1'7, 19281,693,801 Adams Dec. 4, 1928 2,265,184 Miescher et a1. Dec. 9, 19412,351,833 Northey et al. June 20, 1944 2,417,208 Martin et a1 Mar. 11,1947 FOREIGN PATENTS Number 9 Country Date 532,943 Great Britain Feb. 4,1941 220,975 Switzerland Aug. 1, 1942 221,219 Switzerland Aug. 17, 1942221,519 Switzerland Sept. 1, 1942 93,341 Sweden Nov. 19, 1938 70,567Norway June 26, 1946 m one Perkins et al., Chem. Abstracts, vol. 21(1927), page 901.

Arvin et al., Chem. Abstracts, vol. 22 (1929),, page 228.

Certificate of Correction Patent No. 2,538,794

ROBERT BRUCE MOFFETT ET AL.

January 23, 1951 It is hereby certified that error appears in theprinted specification of the above numbered patent requiring correctionas follows:

Column 2, line 33, for alladium-on-chamoal read palladium-on-charooalcolumn 9, line 5, after of, second occurrence, insert a compound of;

and that the said Letters Patent should be read as corrected above, sothat the same may conform to the record of the case in the PatentOflice.

Signed and sealed this 3rd day of April, A. D, 1951.

THOMAS F. MURPHY,

Assistant Oommissz'oner of Patents.

1. A SUBSTANCE OF THE GROUP CONSISTING OF BASIC ESTERS OF THE FORMULA